Cytokines and growth factors

For a drug to be successful, just as important as what the drug does to the body, is what the body does to the drug. Not only is it important to transport therapeutic drugs effectively to where they are needed, but once it is there, they have to remain long enough to have an effect. Studies to understand a drug's journey through the body are in the domain of drug metabolism and pharmacokinetics, usually abbreviated to DMPK.

From 1957 to 1961, Thalidomide, a small molecule drug, was prescribed to treat a range of conditions in pregnant women including morning sickness. The developmental abnormalities that it caused in the developing foetus made the drug synonymous with pharmaceutical negligence. Despite this, in 1988, thalidomide was approved for the safe treatment of leprosy and cancer.

Rapidly increasing public and private research funding is increasing our understanding of the ageing process. This is starting to yield results that could allow therapeutic intervention. Surprisingly, it seems a single cytokine could modulate brain ageing. Could we be on the verge of therapies that will extend the limits of human health?

The development of complex multicellular forms, such as this zebrafish, relies on the activity of morphogen gradients acting differentially on individual cell surface receptors. The way receptors and their ligands present themselves to each other, either dispersed or in clusters, has a dramatic impact on the consequences of their interaction.

Recombinant cytokines and other growth factors underpin cell culture and are as important to biotechnology as semi-conductors are to information technology. They also provide a source of cell-based assay variability. Understanding cytokine dynamics is important to the design of better cell-based assays and manufacturing systems.

In the 1890s, William Coley (pictured) pioneered techniques that boost immune activity against cancer by injecting pathogens into cancer patients to stimulate their immune system. The modern emergence of onco-immunotherapy began with the therapeutic development of cytokines. These messenger proteins modulate both innate and adaptive immunity. Although they have been overshadowed by checkpoint inhibitors for the last decade, there is renewed interest in targeting and harnessing cytokines for cancer immunotherapy.

Mucosal surfaces are the primary interface between an individual and pathogens and are particularly vulnerable to infection. Yet, they also come into regular contact with a host of antigens that need to be tolerated. To allow tolerance and deal with a constant threat of infection, a dynamic and complex array of immune mechanisms provide a finely calibrated first response to these invasive microbial threats.

Cancer drug candidates sometimes emerge with exceptional promise but ultimately fall short. In the late 1990s, endostatin gained huge prominence and was widely viewed as an exceptional cancer drug candidate. But things didn’t quite work out. Although endostatin is now approved by the FDA, in the West it is largely forgotten, eclipsed by newer treatments. But look East, notably to China, and endostatin is very much at the forefront of cancer therapy, particularly in combination with chemotherapy. Why have its fortunes varied geographically and will it ever make a global impact?

Inflammation is critical for maintaining health, but, paradoxically, can also generate disease: Chronic inflammation is strongly associated with the development of cancer and is also a key driver of the ageing process. In addition, auto-immune diseases, of which there are very many, are debilitating and can lead to high rates of morbidity and mortality. Drugs that are able to specifically target the damaging aspects inflammatory responses whilst leaving critical functions intact can be hugely successful.

Why do some people fall seriously ill and die with Covid whilst others are asymptomatic? A remarkable characteristic of Covid-19 is the way it affects individuals so differently: Around 40% of people infected with SARS-CoV-2 are asymptomatic. A further 40% experience mild, upper respiratory tract symptoms. The remaining 20% develop pneumonia, of which 10% will become hypoxic, leading to critical illness in around 3%. In addition to age, sex and underlying health issues, the ability to deploy key immunomodulatory cytokines has emerged as an important risk factor for mortality.